This application seeks renewal of a program that is now in its 35th year. The proposal comprises four scientific projects focused on studies of the mechanisms of hypoxic pulmonary hypertension (PH). The proposed studies are collectively founded on the hypothesis that the pathogenesis of hypoxic PH involves both functional (vasoconstriction and wall stiffening) and structural (vascular wall thickening) components, and that both components involve hypoxia-induced alterations in resident cell function as well as recruitment and interactions with inflammatory and/or progenitor cells. Projects 1, and 3 represent continuation and evolution of current program projects, while Projects 2 and 4 have been added to incorporate complementary new directions and expertise. The projects are highly interactive, both conceptually and in the performance and communication of experimental results, share numerous models and techniques, and are supported by three strong cores: administrative, animal, and tissue. The project leaders, Drs. Stenmark, Nemenoff, Klemm and Geraci have worked together on studies regarding cell signalling and of pulmonary hypertension for many years. The four projects address new and innovative hypotheses regarding the cellular mechanisms of chronic hypoxic PH. Project 1 explores the role of circulating myeloid mesenchymal progenitor cells, fibrocytes, in vascular remodeling and stiffening. Project 2 proposes that the phosphatase PTEN is a potent, endogenously produced inhibitor of SM proliferation and that SM-specific PTEN inactivation is an early and critical trigger driving vascular remodeling. Project 3 investigates how loss of CREB in SMC results in increases in SM proliferation, collagen elastin synthesis and VCAM-1 expression, which ultimately leads to accumulation of monocytes/progenitor cells and remodeling in the pulmonary arterial wall. Project 4 examines the role of disrupted PGI2 and PPAR? signaling in the aberrent cell growth characterizing chronic pulmonary vascular remodeling. These studies will provide new insights into the cellular/molecular mechanisms of chronic hypoxic pulmonary vasoconstriction and vascular stiffening and remodeling and may lead to novel, more effective therapy for hypoxic PH.